Chapter 25 – Hormones of the Cardiovascular System

Updated January 20, 2011

Introduction

Neurohumoral stimulation is a key finding in syndromes such as chronic heart failure (CHF), type-2 diabetes mellitus (T2DM), and chronic kidney disease (CKD). There, the activation of cardiovascular hormonal systems such as the renin-angiotensin II-aldosterone system (RAAS) translates into progression of the underlying disease and/or development of cardiovascular comorbidity associated with an increased risk for major adverse cardiac events. Figure 1 provides an overview of cardiovascular neurohormonal systems pertinent to clinical syndromes such as CHF, T2DM and CKD.
In CHF, epidemiologic data support the notion that plasma levels of norepinephrine [1] and brain-natriuretic peptide (BNP) [2] are reliable markers for patient outcome. Landmark studies have shown that CHF patients benefit from angiotensin-converting-enzyme (ACE) inhibitors, beta-adrenergic blockade, and mineralocorticoid- receptor blockade. Concerning ACE inhibition, the inherent bradykininergic effects appear to be important in the CHF condition, rendering ACE inhibitors superior to angiotensin receptor blockers [3]. Regarding the rationale for beta-adrenergic blockade in CHF, the “Cardiac Insufficiency Bisoprolol Study II” (CIBIS II), amongst other studies, has shown a 34% mortality reduction in patients staged NYHA class III and IV when bisoprolol was added to standard of care therapy [4]. Even after the introduction of beta-adrenergic blockade and ACE inhibition in CHF, an additional improvement in the prognosis of CHF patients has been achieved by mineralocorticoid-receptor blockade as demonstratd by the “Randomized Aldactone Evaluation Study” (RALES) [5] and “Eplerenone Post Acute Myocardial Infarction Efficacy and Survival Study” (EPHESUS) [6].

Beyond CHF, outcome-related research has tested the blockade of neurohumoral pathways in coronary artery disease (CAD) as well: the “Heart Outcomes Prevention Evaluation Study” has proven a 26% reduction in cardiovascular deaths in patients with coronary artery disease without signs of CHF when treated with an ACE inhibitor [7]. Therefore, a direct role for RAAS activation with regard to pathogenesis of CAD and disease progression has been suggested. Animal research suggests angiotensin 2 to promote aortic aneurysm formation [8]. A connection between angiotensin 2 and macrophage and T-lymphocyte infiltration of the arterial vessel wall has been established for aortic-aneurysm formation [9].
Along with a decrease of renal function in CKD, the prevalence of cardiovascular comorbidity and incidence of major adverse cardiac events rises in a linear fashion [10]. There, RAAS activation appears to play a center-stage role [11]. In addition, local hormone activation within the tubul-interstitium, e.g. prostaglandin synthesis [12], may play a further role which remains to be elucidated. In addition, recent data suggest vitamin D supplementation to reduce atherosclerosis in CKD [13], although blood pressure reduction by administering vitamin D is unlikely [14]. In that regard, vitamin D3 appears to control T-cells implicated in the atherosclerotic process [15].
Last, an emerging body of data points at specific states of neurohumoral stimulation in T2DM and its precursor states such as obesity [16]. As type-2 diabetes is tightly connected with obesity, obesity-related mechanisms of insulin resistance and neurohumoral stimulation become subjects of research interest. Besides non-pharmacologic interventions such as increased physical activity and a low-caloric diet, medical interventions influencing appetite and metabolic rate are investigated. The fact that patients with male-type obesity are more prone to developing T2DM than patients with female-type obesity has influenced the definition of metabolic syndrome by the “Third Report of the National Cholesterol Education Program’s Adult Treatment Panel” (ATP III) [17]. There, waist circumference is used instead of body-mass index. Various definitions of metabolic syndrome exist [18]. The established diagnosis of metabolic syndrome predicts the risk for type-2 diabetes (24 fold increased) and for atherosclerosis (3-4 fold increased) [19]. According to a study among 359,387 participants from nine countries in the European Prospective Investigation into Cancer and Nutrition (EPIC), using Cox regression analysis, the optimal waist circumference for women was between 75 and 80 cm, and for men, between 90 and 95 cm. Each increase by 5 cm increased the mortality risk by 17 percent for men, and by 13 percent for women [20]. Neurohumoral mechanisms may offer additional insights into evolution towards T2DM. Among hypertensives treated either with losartan or atenolol in the LIFE study, the losartan-treated branch had a greater benefit in terms of T2DM prevention when compared to the atenolol-treated group while blood-pressure control was equal [21]. That is, specific neurohumoral mechanisms such as the RAAS may be intimately involved in diabetes evolution.
Research issues remain to be solved regarding specific signal cascades involved in specific states of neurohumoral stimulation associated with CHF, CKD, or T2DM. A better understanding of neurohumoral compensatory responses to pathologies may help explain a number of clinical puzzles.
Overall, in this chapter, pertinent cardiovascular hormone actions are being highlighted with regard to hemodynamic actions as documented by alterations of systemic vascular resistance and cardiac output as well as non-hemodynamic effects such as inflammation and oxidative stress.

Actions of cardiovascular hormones

As an overview, hormone consequences are summarized for epinephrine, norepinephrine, brain natriuretic peptide, renin, angiotensin 2, aldosterone, endothelin, and estrogen in Table 1.
Besides hemodynamic effects, chronic inflammation and oxidative stress are focused on as non-hemodynamic effects of hormones pertinent to the cardiovascular system.
Chronic inflammation as a result of cytokine activation may be monitored systemically by measuring C-reactive protein (CrP) released from the liver upon cytokine stimulation, by interleukin-6. An elevated CrP directly translates into a worse cardiovascular prognosis both in patients after myocardial infarction [22], and in apparently healthy persons without prior myocardial infarction, but with elevated CrP > 2 mgl [23]. Therefore, cardiovascular hormone action affecting interleukin pathways as detected by an increased CrP needs to be regarded with scrutiny.
Oxidative stress adversely affects cell function either by direct effects on membranes, proteins or nucleic acids or, indirectly, by scavenging nitric oxide and thereby disturbing vasomotor function. Oxidative stress in disease states such as T2DM may primarily be the result of endogenous sources (Figure 2). Enzymes such as NADPH oxidase, xanthine oxidase, and uncoupled nitric oxidase are able to release reactive oxygen species. In addition, reactive oxygen species may leak from mitochondria. In cardiovascular high-risk patients, in-vitro antioxidants like ascorbic acid or tocopherol do not translate into cardiovascular endpoint reduction [24]. Alternatively, therapies addressing sources of oxidative stress become focus of interest aiming to control the production of reactive-oxygen species and to increase nitric-oxide bioavailability. Medical interventions that lower endogenous oxidative stress include ACE-inhibition [25], Beta Blockade [26], or the use of statins [27,28].
For greater detail, cardiovascular hormones are dealt with individually in the corresponding section.

Table 1: Effects of hormones on the circulatory system.
	Target	SVR	HR	SNS	Oxidative Stress		CRP
Epinephrine	EC,VSMC	(↑↓)	↑	↑		(↑↓)	↑
Norepinephrine	VSMC	↑	↑	↑		↑	↓
BNP	EC,VSMC	↓	↔	↓		ND	ND
Angiotensin 2	EC,VSMC	↑	(↑↓)	↑		↑	↔
Aldosterone	EC,VSMC	↑	↔	ND		↑	↔
Endothelin	VSMC	↑	(↑↓)	↑		↑	↑
Estrogen	EC	↓	↔	↓		↓	↑
SVR, systemic vascular resistance; HR, heart rate; SNS, sympathetic nervous system; CRP, C-reactive protein; EC, endothelial cells, VSMC, vascular smooth muscle cell. Autonomic changes are assessed via HR variability, sympathetic nervous system (SNS) activity, or norepinephrine plasma levels. Oxidative stress is assessed by isoprostane levels in serum. The state of inflammation is assessed by CRP levels

Epinephrine

Epinephrine stimulates α, β1 and β2 receptors in vascular smooth muscle cells. As a consequence, epinephrine increases both ventricular contractility and heart rate, and causes vasoconstriction in the arterioles of the skin, mucosa, and splanchnic areas, thereby increasing blood pressure. However, epinephrine dose-dependently leads to vasodilation in skeletal muscle arterioles as a first-line response to stress. Endothelial cells emerge as a target for epinephrine as well [29]. In addition to well characterized chronotropic and inotropic effects on the heart, epinephrine bears a certain antioxidant potential by increasing both the intra- and extracellular superoxide dismutase, a major oxidant-stress defense. Hydrogen peroxide, the product of the reaction catalyzed by superoxide dismutase still is a reactive oxygen species that is readily disposed of by both catalase and reduced glutathione. The induction of superoxide dismutase by epinephrine, e.g. during vigorous exercise, increases the amount of hydrogen peroxide that, in turn, is a known activator of the endothelial isoform of nitric oxide synthase (eNOS). Increased amounts of nitric oxide promote vasodilation, thereby increasing blood flow, tissue oxygenation and blood-based antioxidative stress defense [30,31]. In addition, epinephrine increases plasma CrP in a dose-dependent manner, probably via a receptor mechanism [32,33].
Coactivation of the sympathetic nervous system may lead to effects indistinguishable from norepinephrine, the primary neurotransmitter of the sympathetic portion of the autonomic nervous system.

Norepinephrine

Norepinephrine is an agonist of α and β1 adrenergic receptors mediating vasoconstriction. Sympathetic nervous system activation leads to norepinephrine spillover from sympathetic nerve terminals and from adrenal medullary cells. Norepinephrine exerts positive inotropic and chronotropic effects to the heart, increased peripheral vascular resistance, thereby increasing blood pressure. However, increases in blood pressure may attenuate chronotropy via a baroreflex mechanism. On the level of adipocytes, norepinephrine mediates body-temperature increasing effects [34]. Norepinephrine increases oxidative stress [35]. Sympathetic denervation worsens a lipopolysaccharide-induced rise of interleukin-6 and, consecutively, CRP. Therefore, one can conclude that the sympathetic nervous system including its main transmitter, norepinephrine, helps inhibit pro-inflammatory stimuli [36].

Brain Natriuretic Peptide

BNP is a key cardiovascular peptide hormone that is derived mainly from the left ventricle upon increased wall stress [37]. Brain natriuretic peptide (BNP) belongs to a family of at least 3 members: atrial natriuretic peptide (ANP), BNP, and C-type natriuretic peptide (CNP) that exert local and humoral effects on blood pressure and extracellular body-fluid volume via vasodilation and natriuresis [38]. BNP binds to Natriuretic Peptide Receptors (NPR A–C) evoking an intracellular increase of cyclic guanosine monophosphate (cGMP), a second messenger that is shared by substances like nitric oxide. NPR´s are found in vascular smooth muscle cells, endothelial cells, heart, adrenal gland, and in the kidney. Cleavage of BNP is widely maintained by neutral endopeptidases.  BNP release is more pronounced in acute heart failure [39], and acute myocardial infarction [40]. For differentiating causes of dyspnea, BNP measurement was shown to be beneficial in the emergency setting [41]. In chronic heart failure, therapy may be optimized by serial BNP measurements aiming for the lowest level possible [42,43]. Although BNP lowers blood pressure due to less systemic vascular resistance and cardiac filling pressures, no reflex increase of sympathetic activation occurs with resulting increases of heart rate. This is explained by a BNP-induced resetting of the baroreflex, by an antisympathetic mechanism, or both [44].
BNP promotes peripheral arteriolar vasodilation dose–dependently, thereby reducing cardiac filling pressures [45]. BNP antagonizes aldosterone [46] and blunts renin-angiotensin-aldosterone activation following furosemide in heart failure [47]. Plasma BNP is a diagnostic tool in heart failure because it correlates with the NYHA class of dyspnoe in chronic heart failure [48].
The role for nesiritide, a recombinant form of BNP, in therapy of acute or chronic heart failure, still is under investigation.

Renin, Angiotensin 2

Renin, an aspartyl protease synthesized by the precurse molecule (pro)renin, is able to cleave angiotensinogen to form Angiotensin 1 at the origin of the angiotensin peptide cascade. Renin is released from renal juxtaglomerular cells into the circulation by sympathetic –nervous-system activation, dopamine, and low sodium concentrations. In addition, renin expression is inhibited by vitamin-D receptor activation [49]. Besides catalyzing angiotensin-1 formation, both (pro)renin and renin exert biological effects via receptors within the kidneys, and a mitogen activated protein-kinase (MAPK) pathway [50].

A nonpeptide compounds (Aliskiren) has been marketed to block enzymatic activity of Renin since 2007. In addition to ACE inhibitors or angiotensin receptor blockers (ARB’s), a more comprehensive RAAS blockade can be achieved that allows for a more effective attenuation of proteinuria in chronic renal insufficiency both in an animal model (41) and in T2DM patients [51]. As one underlying reason, direct renin inhibition preserves renal podocyte function in T2DM [52].

Angiotensin 2 is a powerful vasoconstricting octapeptide cleaved from angiotensin 1 by ACE-1. Neutral endopeptidases favor the formation of angiotensin 1-7 and angiotensin 1-5. Both molecules exert ACE inhibition. In addition, angiotensin 1-7 mediates vasodilation through a receptor mechanism counteracting vasoconstriction mediated by angiotensin 2 [53,54]. Angiotensin 2 has been linked to cardiac hypertrophy and fibrosis, thus inhibiting substrate formation or directly blocking its receptor, the angiotensin 2 Type 1 receptor, has become a hallmark of treatment in cardiovascular medicine. Angiotensin 2 effects including increased plasma CrP levels may be due to local activation of endothelin [55]. Angiotensin increases oxidative stress [35]. Central angiotensin 2 is considered to be a potent activator of the sympathetic nervous system [56].

Besides hypertension, ACE inhibition has become a corner-stone therapy in CHF, CAD, diabetes mellitus, and in chronic kidney disease.

In CKD, both ACE inhibitor and ARB montherapy were demonstrated to be beneficial in the “Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial“ (ONTARGET). However, combination therapy with ACE inhibitor and ARB were not superior to either monotherapy in CKD patients without proteinuria of more than 1 g per day [57].

Aldosterone

Aldosterone is the major human mineralocorticoid produced in the adrenal cortex. In certain conditions, it may also be locally released in both heart and vasculature [58,59] affecting myocytes in a paracrine way. In the healthy rat heart, however, the level of aldosterone is low, reflecting plasma levels in intact rats [60].
The adrenal secretion of aldosterone is stimulated mainly by angiotensin 2, by potassium and, less potently, by corticotropin. An increase in serum potassium by 0.1 mmol/L can elevate aldosterone by 35%, whereas a fall in serum potassium of 0.3 mmol/L can reduce plasma aldosterone by 46% [61,62]. Chronically increased plasma corticotropin concentrations as in patients with congestive heart failure, may increase aldosterone secretion [63]. Aldosterone increases blood pressure via increased sodium reabsorption. Atrial natriuretic peptide, BNP, and dopamine inhibit aldosterone secretion.
Aldosterone binds to the cytoplasmic and transmembrane mineralocorticoid receptor inducing both genomic and non-genomic actions in targets like endothelial cell, vascular smooth muscle cells, the kidney, colon, salivary glands, heart, and the brain [64]. Novel nonepithelial effects of aldosterone are mediated via a second messenger system which involves activation of the sodium/hydrogen antiporter [65]. Aldosterone regulates renal tubular sodium absorption and transcription of sodium-potassium ATPase. After a few days of extracellular fluid expansion by increased aldosterone levels, the individual is protected from continous fluid expansion through an “escape” mechanism which denotes attaining a new sodium balance and the formation of a new steady state. Aldosterone-mediated effects include increased oxidative stress, apoptosis, cardiac fibrosis, as well as left-ventricular hypertrophy [66]. CrP is not affected by mineralocorticoid-receptor blockade [67].
Randomized clinical trials demonstrated aldosterone to play an important role in heart failure. In RALES, treatment with the aldosterone antagonist spironolactone was shown to reduce mortality by 30 % without affecting blood pressure in patients with NYHA class III and IV [5]. Likewise, for post-myocardial-infarction heart failure patients in EPHESUS, the more specific aldosterone antagonist eplerenone was proved to reduce total mortality by 26 % [6]. In both studies, the heart failure patients were receiving otherwise optimal medications including aspirin, statin, beta-blocker, ACE inhibitors or ARB’s as well as a reperfusion strategy within 14 days after the index acute coronary event in EPHESUS. Hypothetically, the mineralocorticoid-receptor blockade helps prevent cardiac sudden death either by elevating potassium concentrations, thereby reducing the risk for incessant ventricular arrhythmias via direct effects on cardiac remodelling. Of note, mineralocorticoid receptor blockade had been shown to be efficacous in clinical trials in patients with hypertension and heart failure in spite of low/low normal plasma aldosterone [68].

Endothelin

The vasculature, namely the endothelium, is able to release the vasoconstrictor endothelin-1, thus determining vascular tone along with endothelial vasodilators such as nitric oxide, hyperpolarizing factor, and prostacyclin. Endothelin-1 (ET-1) is the most widely distributed member of the endothelin family (Figure 3). ET-1 generation depends on endopeptidase and endothelin converting enzyme (ECE) activity. Neutral endopeptidases also catalyze the generation of the vasodilator Angiotensin 1-7 as well as the cleavage of BNP, whereas ECE is activated by Angiotensin 2, thus demonstrating the close relationship between these vasoconstrictors.
In addition to vasoconstriction, ET-1 is sympatho-excitatory in the central nervous system [69]. Moreover, ET-1 supports angiotensin 2-induced aldosterone activation [70]. Finally, endothelin-1 promotes interleukin-6 and CrP activation [71].

Estrogen

Acknowledging that gender differences in longevity and in the onset of cardiovascular disease may be due to sex hormone differences, hormone replacement therapy has been considered one option for women with early menopause either naturally occuring or surgically induced. In hysterectomized women Estrogen therapy has been demonstrated to be more favorable in terms of lipid state than combined estrogen/progestin hormone substitution. However, estrogen therapy increased CrP as shown in the PEPI trial [72]. No effect has been found with regard to hemodynamics at rest [73]. Randomized clinical trials with postmenopausal women using either a combined hormone replacement therapy or unopposed estrogen replacement therapy both for secondary [74] and for primary [75] prevention of myocardial infarction were stopped prematurely due to the worse outcome in the treatment groups. However, the estrogen-alone hormone-replacement-therapy arm of the Women Health Initiative (hysterectomized women) showed promising data [76]. At present, current guidelines restricting hormone replacement therapy to moderate or severe postmenopausal symptoms, will not be extented to primary or secondary cardiovascular protection [77].
Testosterone can be converted peripherally and in fatty tissue to estradiol via aromatase which is especially important when considering the current obesity epidemic. Obese men are often found to be type 2 diabetics and may concomitantly suffer from testosterone deficiency syndrome [78, 79].  As with many things, it is hard to find Aristotel’s middle, i.e. which testosterone level would be best for each individual “patient”. Similarly, both growth hormone excess and growth hormone deficiency may put individuals having either of these conditions at a higher cardiovascular risk.

Summary

Cardiovascular hormones play an important role in homeostasis processes in the healthy organism and may become therapeutic targets in clinical syndromes such as CHF, coronary artery disease, CKD, or T2DM. Each of these clinical syndromes is characterized by specific states of neurohumoral stimulation arising from attempts to counteract pathophysiologic dysregulations. In everyday medicine, combinations of the aforementioned clinical entities/syndromes are often encountered. Even though therapies targeting hormone effects may not cure the underlying disease, exaggerated hemodynamic and non-hemodynamic hormone effects may be attenuated, thereby improving prognosis and/or quality of life.
Non-hemodynamic consequences of states of neurohumoral stimulation like inflammation and oxidative stress contribute to cardiac fibrosis and left ventricular thickening that, in turn, may lead to electrical instability and susceptibility for possibly life-threatening cardiac arrhythmias. A neurohumoral blockade, in turn, may primarily achieve a more stable and economic cell metabolism by changes in oxygen demand, in prevalent oxidative stress and inflammation. This, in turn, may slow down disease evolution. However, the exact state of neurohumoral stimulation greatly depends on the underlying pathology.
For both CKD [11] and CHF [80], neurohumoral activation may represent a final common pathophysiologic pathway. Therapies designed to attenuate neurohumoral activation in CHF actually counteract a vicious cycle because the very consequences of neurohumoral stimulation include increased oxidative stress that, in turn, may aggravate neurohumoral stimulation [81]. 
Hormonal mechanisms are involved in coronary-artery disease progression as well involving systemic chronic inflammation [82] and oxidative stress [83] are promoted.
In T2DM, adipokines and inflammatory cytokines appear to play a central role in the development of insulin resistance [84,85]. Adipokines involved with thrombosis include thrombospondin-1 (TSP1) and plasminogen activator inhibitor 1 (PAI1). TSP1 is expressed by adipose tissue. It activates TGF-beta. TGF-beta is also activated by angiotensin II and high glucose. TGF-beta activates PAI-1, a procoagulant with an important role in atherosclerosis [86]. Regarding cytokine stimulation in T2DM, oxidative stress e.g. from repetitive hyperglycemia [87] may fuel this process.